DESCRIPTION (provided by investigator): A subset of premenopausal women is at significantly elevated risk for breast cancer due to specific genetic traits (e.g. BRCA1 or 2 mutations) and or strong family history. Effective breast cancer prevention available for high-risk women (drugs or surgery) are hormonal interventions;the strongest basis for breast cancer prevention among high risk women is through hormonal intervention. However, both surgical and drug based prevention have serious negative long term consequences that may not be acceptable to many women. We propose a preventive exercise intervention for increased risk women that might address the same hormonal issues, yet have fewer serious side effects and not impact negatively on quality of life. Exercise training also has many well established positive health benefits beyond those hypothesized herein. These women are highly motivated to reduce their risk. Therefore, even if the alteration in risk is marginal (e.g. consistent with smaller tumor size, delayed onset of breast cancer, or reduced breast density that would improve the success of early screening), women at increased risk deserve to know what they can reasonably expect from regular exercise with regard to reducing breast cancer risk. The overarching goal of the proposed dose response trial is to establish the effects of 5 months of low or high dose exercise on variables known to be associated with breast mitotic activity, among a cohort of 160 women with a >18 percent lifetime risk for breast cancer. The exercise doses were chosen to approximate the current public health guidelines for health promotion (150 minutes weekly) and weight control (300 minutes weekly). The primary hypothesis to be tested is that exercise training will result in a significant decrease of estrogen exposure, and in a dose response manner. The measurement of estrogen exposure is a particular innovation of the proposed work compared to prior studies that have examined the effects of exercise on estrogens. Daily spot urinary samples will be collected over 2 menstrual cycles before and after the exercise training intervention and the primary outcome will be total hormone exposure as assessed by estrogen area under the curve. Study measures include known mitogens (e.g. daily urinary estrogen and progesterone over multiple menstrual cycles;estrogen metabolites;other sex steroid hormones), as well as fibroglandular tissue volume from MRI scans (as a surrogate of breast mitotic activity). Changes in body composition and adipokines will also be assessed. In combination with data from an ongoing parallel trial in low risk women (the WISER study), the proposed work will provide novel information regarding differences, or lack thereof, in levels of commonly accepted risk factors for breast cancer (estrogens, estrogen metabolism, other sex steroid hormones, adipokines, and body composition), as well as comparisons of the effects of exercise training on these outcomes. PUBLIC HEALTH RELEVANCE: WISER Sister is a randomized controlled trial that will add significantly to understanding the potential for five months of exercise training to reduce breast cancer risk factors (including estrogens and MRI breast imaging) in 160 young women (aged 18-35) with significantly increased risk. In combination with data from an ongoing parallel trial in low risk women (the WISER study), the proposed work will provide novel information regarding differences, or lack thereof, in levels of commonly accepted risk factors for breast cancer (estrogens, breast density from MRI, estrogen metabolism, other steroid hormones, adipokines, and body composition), as well as comparisons of the effects of exercise training on these outcomes. The WISER Sister study will randomize 160 young women with elevated breast cancer risk into 3 equal sized groups: wait list control, low dose exercise (150 minutes weekly, to approximate the current public health recommendations for exercise for general health promotion), and high dose exercise (building to 300 minutes weekly, to approximate the public health recommendations for weight control).